The Severity and Frequency of Systemic Reactions to Hazelnut Are Significantly Higher in Hazelnut Allergic Patients Monosensitized to Cor a 8 than in Patients Polysensitized to Cor a 1, Cor a 8, and Cor a 9.

INTRODUCTION: Hazelnuts are a leading trigger of food allergy. To date, several molecular components of hazelnut are available for component-resolved diagnosis. However, little is known about how simultaneous sensitization to multiple allergens affects the severity of the hazelnut-induced reaction. In a previous study, our group demonstrated a lower risk of systemic reactions to peach in patients sensitized to both Pru p 3 and Pru p 1 than in the patient monosensitized to peach LTP. We aimed to assess whether this was also true in hazelnut allergy in a cohort of adult patients. METHODS: Patients were selected based on a history of symptoms such as urticaria, vomiting, diarrhea, asthma, and anaphylaxis indicative of hazelnut IgE-mediated food allergy and graded according to a clinical severity scale. For all patients, specific IgE was determined for Cor a 1 and Cor a 8 and, for most patients, also Cor a 9. Patients were offered an oral food challenge in open format (OFC) with a cocoa-based roasted hazelnut spread on a voluntary basis in order to prescribe an appropriate diet. RESULTS: A total of two hundred and fourteen patients were recruited. Among these, 43 patients were monosensitized to Cor a 8. One hundred and seventy-one patients were sensitized to Cor a 1 (79.9%), and, among them, 48/171 (28.1%) were also Cor a 8 positive. Cor a 9 was evaluated in 124/214 patients, testing positive in 21/124 (16.9%). Patients monosensitized to Cor a 8 experienced systemic reactions more frequently than those sensitized to Cor a 1 ± Cor a 8 (p < 0.00001), with significantly more severe reactions (p < 0.0005) and testing more frequently positive at OFC (p < 0.0001). Regarding Cor a 9, the sensitized patients were significantly younger (p = 0.0013) and showed reactions of similar severity to patients who tested Cor a 9 negative, and these reactions were milder than in patients monosensitized only to Cor a 8. DISCUSSION/CONCLUSION: Sensitization to Cor a 1 seems to protect from the development of the severe systemic reactions induced by Cor a 8 sensitization, Cor a 9 does not influence the severity of symptoms in adult patients. The OFC with roasted hazelnut may help in dietary guidance.

Cutaneous melanoma in older patients.

BACKGROUND: In industrialized countries, the aging population is steadily rising. The incidence of cutaneous malignant melanoma (CMM) is highest in old people. This study focuses on the clinicopathological profile of CMM and indicators of diagnostic-therapeutic performance in older patients. METHODS: This retrospective population-based cohort study included 1,368 incident CMM, as recorded in 2017 by the Regional Veneto Cancer Registry (Northeast Italy). Older subjects were defined as ≥ 80, old as 65-79, and adults as < 65 years of age. The strength of association between pairs of variables was tested by Cramer's-V. Using age groups as the dependent variable, ordered logistic regression was fitted using the clinicopathological CMM profiles as covariates. In each of the three age-groups, the indicators of clinical performance were computed using the Clopper-Pearson exact method. RESULTS: Compared to patients aged younger than 80 years (1,187), CMM in older patients (181; 13.2%) featured different CMM topography, a higher prevalence of ulcers (43.3% versus 12.7%; p < 0.001), a higher Breslow index (p < 0.001), a lower prevalence of tumor-infiltrating lymphocytes (64.4% versus 76.5%, p < 0.01), and a more advanced pTNM stage at clinical presentation (p < 0.001). Elderly patients with a positive sentinel-lymph node less frequently underwent sentinel- lymph node biopsy and lymphadenectomy (60.0% versus 94.2%, and 44.4% versus 85.5%, respectively; p < 0.001). CONCLUSIONS: In older CMM patients, the clinicopathological presentation of CMM shows a distinctive profile. The present results provide critical information to optimize secondary prevention strategies and refine diagnostic-therapeutic procedures tailored to older patients.

Prevalence of metabolic syndrome and its association with rapid weight loss among former elite combat sports athletes in Serbia.

BACKGROUND: In terms of the potential influence of rapid weight loss (RWL) on the metabolic health of former combat sports athletes (CSA), the scientific literature is quite scarce. Therefore, the objective of the presented research was to determine the differences in metabolic syndrome (MetS) parameters and the prevalence of MetS between former athletes who performed RWL and athletes who did not. METHODS: The sample of the presented study comprised 150 participants from Serbia, equally divided into two groups: 75 former athletes who had practiced combat sports and 75 ex-athletes of various other sports who did not practice RWL during their careers. The following parameters related to the MetS were evaluated: waist circumference, high-density lipoprotein cholesterol, systolic blood pressure, diastolic blood pressure, fasting glucose, and triglycerides. The oral glucose tolerance test (OGTT) was used to assess the participant's body response to sugar. RESULTS: The RWL group had significantly higher both systolic (p < 0.001) and diastolic blood pressure (p < 0.001) compared to the group of athletes who did not practice weight reduction during their careers. Additionally, a tendency toward statistically significant differences between groups was recorded in the variable triglycerides (p = 0.069). Regarding OGTT, increased values of fasting blood glucose at the final measurement were revealed only in the RWL group (p = 0.003). The prevalence of MetS was substantially higher in CSA than in the control group (39.5% vs. 16.2%, respectively p = 0.002). CONCLUSIONS: This study suggests that former elite CSA who used RWL during their sports career are susceptible to negative metabolic alterations at the end of their competitive period.

Cutaneous melanoma in adolescents and young adults.

BACKGROUND: Cutaneous malignant melanoma (CMM) ranks among the five most common cancers in young people in high-income countries and it features peculiar clinicopathological traits. Very few studies have addressed the quality of care and the costs for adolescents and young adults (AYA) population. OBJECTIVE: To provide a comprehensive epidemiological and clinicopathological profile of CMM in AYA. The study also addresses the cost-of-illness and the diagnostic-therapeutic performance indicators by patient age category. METHODS: This population-based cohort study included 2435 incident CMM (age range 15-65 years; age 15-39 = 394; age 40-65 = 2041), as recorded in 2015, 2017 and 2019 by the Regional Veneto Cancer Registry (Italy). Cramer's-V tested the strength of association between pairs of variables. The Kaplan-Meier method was used to test the association between age and survival rate. The clinical performance indicators were computed using the Clopper-Pearson exact method. RESULTS: In AYA patients (16.2%), CMM incidence rates increased significantly from 1990 to 2019. Low-stage CMM (p = 0.007), radial growth pattern (p = 0.026) and lower Clark levels (p = 0.007) prevailed; males had less advanced malignancies (p = 0.003), with the trunk as the most common primary site (67.5%); the lower limbs (32.6%) were the most common primary site for females (p < 0.001). Overall survival was better in AYA than adults. No significant difference was detected in the clinical management of the two age groups, with the only exception of the margin in wide local excision. The care costs were lower in AYA (€195.99 vs. €258.94, p = 0.004). CONCLUSION: In AYA patients, the CMM clinicopathological presentation shows a distinctive profile. The present results provide critical information for optimizing primary and secondary prevention strategies and for tailoring diagnostic therapeutic procedures to the peculiar profile of AYA CMM patients.

Left Ventricular Hypertrophy in Male and Female Judo Athletes.

Changes in cardiac geometry develop after intense and prolonged training. Left ventricular enlargement, increased relative wall thickness, and growing mass of the left ventricle occur after strenuous exercise. Combat sports such as judo can lead to left ventricular hypertrophy. Previous studies have found that there are differences in left ventricular chamber size and thickness between the sexes, with female athletes having smaller wall diameters and less hypertrophy than male athletes. The research aims to examine heart muscle adaptations and remodeling of cardiac geometry among elite judo athletes and to evaluate differences between males and females. A cross-sectional study included a group of 19 (males n=10, females n=9) professional judokas between 20 and 30 years. Demographic and anthropometric data were collected. Cardiac geometry was determined by two-dimensional transthoracic echocardiography. In terms of left ventricular mass and the left ventricular mass index significant differences were found between male and female judokas (233.44±68.75 g vs. 164.11±16.59 g, p=0.009), (105.16±24.89 vs. 84.66±15.06, p=0.044), respectively. A greater enlargement of the heart muscle is observed in male athletes compared to the female group. Left ventricle enlargement is likely to occur among elite-level judokas.

Immunotherapy with Pru p 3 for food allergy to peach and non-specific lipid transfer protein: a systematic review.

BACKGROUND: Non-specific lipid-transfer protein (nsLTP) is a pan-allergen in the plant world, and a cause of significant concern as food allergen in the Mediterranean area, due to its general heat- and acid-resistance and hence the risk of severe allergic reactions. Pru p 3, the peach nsLTP, is considered the primary sensitizer to this allergen family and this allergy is usually persistent. Allergen-free diet and acute treatment of manifestations are the main recognized management goals in food allergy. MAIN TEXT: The role of immunotherapy for treating food allergy in adult patients is controversial, but immunotherapy for Pru p 3 could potentially represent a relevant therapeutic strategy. We systematically searched databases for studies assessing the role of immunotherapy Pru p 3 in food allergy. Overall, nine studies were included. Immunotherapy with Pru p 3 appears to be effective and with a good safety profile in both peach and LTP allergy for some foods, such as peanut, in both RCT and real-life studies. CONCLUSIONS: Immunotherapy with Pru p 3 is a possible treatment option for food allergy to the peach LTP in the Mediterranean area, although at present have not reached routinary clinical practice. Larger studies are needed to confirm these findings and identify predictive biomarkers.

Clinical Features of Wheat Allergy Are Significantly Different between Tri a 14 Sensitized Patients and Tri a 19 Sensitized Ones.

INTRODUCTION: Wheat is the most important cereal for human nutrition but its high consumption is associated to an increasing complaint of wheat-related disorders, many of which are allergic in nature and different in respect to the involved allergens. In this study, we compared the clinical aspects of wheat allergy presented by patients sensitized to Tri a 19 in respect to those presented by patients sensitized to Tri a 14. METHODS: With this aim, we selected patients sensitized to 1 or both of the 2 allergens, and among these we identified those who were really wheat allergic and reactive on the basis of a standardized methodology. We evaluated the clinical features such as the kind and severity of symptoms, the coexistence of triggering factors such as physical exercise and NSAIDs and alcohol consumption, and the association with other allergens and with various immunologic parameters. Wheat allergy in Tri a 19 sensitized patients was confirmed through a questionnaire while the patients sensitized to Tri a 14 underwent wheat challenge with 100 g of pasta followed by exercise on a treadmill. RESULTS: Seventy-nine patients sensitized to Tri a 14 and 40 patients sensitized to Tri a 19 were recruited. The 2 sensitizations were independent with a significant inverse relation (p < 0.00001). The Tri a 19 sensitized patients presented, in respect to the Tri a 14 sensitized ones, an older age (p = 0.0017), a higher risk to be wheat allergic (p < 0.0001), a higher severity of the reactions (p < 0.00001) and a higher association with some cofactors, namely alcohol (p < 0.0005) and physical exercise (p = 0.003). On the contrary, Tri a 14 sensitization was associated with atopy (p < 0.0001), with a higher probability of patients being asymptomatic (p < 0.0001) and being sensitized to other foods, in particular to nuts and cereals (p < 0.00001). CONCLUSIONS: Sensitization to Tri a 19 or Tri a 14 determines different clinical pictures. In particular, sensitization to Tri a 19 implies a higher probability of severe reactions, even dependent on daily triggers, while that to Tri a 14 implies a higher cross-reactivity with other foods but it's more frequently asymptomatic, making a food challenge necessary to prevent useless food avoidance.

Gender-specific associations between polymorphisms of the circadian gene RORA and cutaneous melanoma susceptibility.

BACKGROUND: Melanoma is the deadliest of skin cancers and has an increasing annual incidence worldwide. It is a multi-factorial disease most likely arising from both genetic predisposition and environmental exposure to ultraviolet light. Genetic variability of the components of the biological circadian clock is recognized to be a risk factor for different type of cancers. Moreover, two variants of a clock gene, RORA, have been associated with melanoma patient's prognosis. Our aim is to test the hypothesis that specific single nucleotide polymorphisms (SNPs) of the circadian clock genes may significantly influence the predisposition to develop cutaneous melanoma or the outcome of melanoma patients. METHODS: We genotyped 1239 subjects, 629 cases of melanoma and 610 healthy controls in 14 known SNPs of seven selected clock genes: AANAT, CLOCK, NPAS2, PER1, PER2, RORA, and TIMELESS. Genotyping was conducted by q-PCR. Multivariate logistic regression was employed for susceptibility of melanoma assessment, modeled additively. Subgroup analysis was performed by gender. For the female subgroup, a further discrimination was performed by age. For prognosis of melanoma assessment, multivariate Cox proportional hazard regression was employed. The Benjamini-Hochberg method was utilized as adjustment for multiple comparisons. RESULTS: We identified two RORA SNPs statistically significant with respect to the association with melanoma susceptibility. Considering the putative role of RORA as a nuclear steroid hormone receptor, we conducted a subgroup analysis by gender. Interestingly, the RORA rs339972 C allele was associated with a decreased predisposition to develop melanoma only in the female subgroup (OR 0.67; 95% CI 0.51-0.88; P = 0.003) while RORA rs10519097 T allele was associated with a decreased predisposition to develop melanoma only in the male subgroup (OR 0.62; 95% CI 0.44-0.87; P = 0.005). Moreover, the RORA rs339972 C allele had a decreased susceptibility to develop melanoma only in females aged over 50 years old (OR 0.67; 95% CI 0.54-0.83; P = 0.0002). None of the studied SNPs were significantly associated with the prognosis. CONCLUSIONS: Overall, we cannot ascertain that circadian pathway genetic variation is involved in melanoma susceptibility or prognosis. Nevertheless, we identified an interesting relationship between melanoma susceptibility and RORA polymorphisms acting in sex-specific manner and which is worth further future investigation.

The surgical treatment of non-metastatic melanoma in a Clinical National Melanoma Registry Study Group (CNMR): a retrospective cohort quality improvement study to reduce the morbidity rates.

BACKGROUND: Reproducible, high-quality surgery is a key point in the management of cancer patients. Quality indicators for surgical treatment of melanoma has been presented with benchmarks but data on morbidity are still limited. This study presents the quality indicators on morbidity after surgical treatment for non-metastatic skin melanoma in an Italian registry. METHODS: Data were extracted from the Central National Melanoma Registry (CNMR) promoted by the Italian Melanoma Intergroup (IMI). All surgical procedures (WE, SNLB or LFND) for non-metastatic skin melanoma between January 2011 and February 2017 were evaluated for inclusion in the study. Only centers with adequate completeness of information (> 80%) were included in the study. Short-term complications (wound infection, dehiscence, skin graft failure and seroma) were investigated. RESULTS: Wound infection rate was 1.1% (0.4 to 2.7%) in WE, 1.3% (0.7 to 2.5%) in SLNB and 4.1% (2.1 to 8.0%) in LFND. Wound dehiscence rate was 2.0% (0.8 to 5.1%) in WE, 0.9% (0.2 to 3.0%) in SLNB and 2.8% (0.9 to 8.6%) in LFND. Seroma rate was 4.2% (1.5 to 11.1%) in SLNB and 15.1% (4.6 to 39.9%) in LFND. Unreliable information was found on skin graft failure. CONCLUSIONS: Our findings contribute to available literature in setting up the recommended standards for melanoma centers, thus improving the quality of surgery offered to patients. A consensus on the core issues around surgical morbidity is needed to provide practical guidance on morbidity prevention and management.

Basal Tryptase High Levels Associated with a History of Arterial Hypertension and Hypercholesterolemia Represent Risk Factors for Severe Anaphylaxis in Hymenoptera Venom-Allergic Subjects over 50 Years Old.

INTRODUCTION: Allergy to Hymenoptera venom (HV) may lead to life-threatening anaphylaxis. Some of the factors influencing the symptom's severity are still undetermined. The aim of this study was to identify the clinical aspects associated with the most severe reactions in a population with HV allergy, by comparing clinical and immunochemical biomarkers between patients with previous local large reactions (LLRs) and systemic reactions (SRs). METHODS: We selected adult patients with a history of HV allergy, with positive diagnostic tests and a correlation with one single Hymenoptera species. Age, gender, atopy, serum basal tryptase (sBT) value, total IgE, venom-specific IgE, history of hypertension, cardiovascular diseases, and hypercholesterolemia were compared between patients with previous LLRs and SRs. RESULTS: 460 adult patients (381 SRs, 79 LLRs) were included. Age (p = 0.0097), male gender (p < 0.0001), arterial hypertension (p = 0.046), hypercholesterolemia (p = 0.009), and higher sBT levels (p = 0.0004) were significantly associated with severe reactions as independent variables. Moreover, considering the previous variables as risk factors, there was a significant and progressive increase in the odds of being Mueller III + IV as the number of positive variables increased. Patients with sBT ≥6.4 ng/mL adjusted for any of the positive variables had increased the risk of Mueller grade IV reaction (p < 0.0001). CONCLUSION: According to our results, older age, male gender, arterial hypertension, hypercholesterolemia, and increased levels of sBT ≥6.4 ng/mL are risk factors for severe anaphylaxis to HV in adults. Atopy and allergic asthma do not increase the risk of HV-induced SRs.

Management of melanoma patients during COVID-19 pandemic in an Italian skin unit.

Due to the COVID-19 crisis, many scheduled medical and surgical activities have been suspended. This interruption to the healthcare system can negatively affect the diagnosis and management of melanoma. Neglecting melanoma throughout the outbreak may be associated with increased rates of mortality, morbidity, and healthcare expenses. We performed a retrospective review of all dermatological and surgical activity performed in our Melanoma Skin Unit between 23 February 2020 and 21 May 2020 and compared these data with those from the same period in 2019. During the lockdown period, we observed a decrease in dermatologic follow-up (DFU) (-30.2%) and in surgical follow-up (SFU) (-37%), and no modification of melanoma diagnosis (-3%). Finally, surgical excisions (SE) (+ 31.7%) increased, but sentinel lymph node biopsy (SLNB) (-29%) and lymph node dissections(LND) (-64%) decreased compared to the same period in 2019. Our experience supports the continuation of surgical and diagnostic procedures in patients with melanoma during the COVID-19 pandemic. Surgical and follow-up procedures for the diagnosis and treatment of melanoma should not be postponed considering that the pandemic is lasting for an extended period.

Oncological outcome of videoscopic groin dissection for lymph node metastasis from melanoma.

BACKGROUND: Videoscopic inguinal lymphadenectomy (VIL) represents an innovative approach for patients with melanoma lymph node (LN) metastases, mainly aimed at lowering wound-related morbidity. However, long-term data on oncologic safety are still lacking. The aim of this study is to review the oncologic outcome of videoscopic groin dissection in a single institution caseload. METHODS: Data were prospectively gathered on patients with inguinal melanoma metastasis who underwent VIL. Clinical data included age, race, sex, tumor histology, node counts and number of metastatic nodes. Disease-free survival and overall survival were monitored based on an institutional follow-up schedule. The study was approved by the local ethics committee (Video-SIIO II study). RESULTS: We analyzed 48 videoscopic groin dissections performed in 50 patients (2 patients underwent bilateral VIL). Median age was 54.5 years. Female/male ratio was 15/33. Indication for surgery was positive inguinal sentinel biopsy and cytological confirmed clinical disease in 40 and 10 cases, respectively. Median LN retrieval count was 19. After a median follow-up of 28 months, groin recurrence (lymphatic basin) was observed in one single case. CONCLUSIONS: VIL for melanoma LN metastases is associated with a favorable oncologic outcome. In particular, LN yield and locoregional recurrence rate obtained with videoscopic dissection are comparable to those reported with the open technique. Prospective studies are needed to confirm these results in a larger cohort of patients.

Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma.

BACKGROUND: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. METHODS: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. RESULTS: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

A case report of toxic epidermal necrolysis (TEN) in a patient with COVID-19 treated with hydroxychloroquine: are these two partners in crime?

BACKGROUND: Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is the most Serious Cutaneous Adverse Reaction (SCAR) often with a fatal outcome. Coronavirus Disease (COVID-19) is caused by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-COV2) and is an emergent pandemic for which no cure exist at the moment. Several drugs have been tried often with scant clinical evidence and safety. CASE PRESENTATION: Here we report the case of 78-years-old woman with cardiometabolic syndrome and COVID-19. A multidrug regimen including others hydroxychloroquine, antibiotics, dexamethasone and paracetamol, low-molecular-weight-heparin and potassium canrenoate was started. After almost 3 weeks, the patient started to display a violaceous rash initially involving the flexural folds atypical targetoid lesions and showing a very fast extension, blister formation and skin detachments of approximately 70% of the total body surface area and mucous membranes involvement consistent with toxic epidermal necrolysis (TEN). The ALDEN algorithm was calculated inserting all drugs given to the patient in the 28 days preceding the onset of the skin manifestations. The highest score retrieved was for hydroxychloroquine. Other less suspicious drugs were piperacillin/tazobactam, ceftriaxone and levofloxacin. CONCLUSIONS: To our knowledge, this is the first case of TEN in a patient suffering from COVID-19 probably associated with hydroxychloroquine. Given the activation of the immune system syndrome induced by the virus and the widespread off-label use of this drug, we suggest a careful monitoring of skin and mucous membranes in all COVID-19 positive patients treated with hydroxychloroquine in order to early detect early signs of toxicities.

CGMD Platform: Integrated Web Servers for the Preparation, Running, and Analysis of Coarse-Grained Molecular Dynamics Simulations.

Advances in coarse-grained molecular dynamics (CGMD) simulations have extended the use of computational studies on biological macromolecules and their complexes, as well as the interactions of membrane protein and lipid complexes at a reduced level of representation, allowing longer and larger molecular dynamics simulations. Here, we present a computational platform dedicated to the preparation, running, and analysis of CGMD simulations. The platform is built on a completely revisited version of our Martini coarsE gRained MembrAne proteIn Dynamics (MERMAID) web server, and it integrates this with other three dedicated services. In its current version, the platform expands the existing implementation of the Martini force field for membrane proteins to also allow the simulation of soluble proteins using the Martini and the SIRAH force fields. Moreover, it offers an automated protocol for carrying out the backmapping of the coarse-grained description of the system into an atomistic one.

Growth rate and myofibroblast differentiation of desmoid fibroblast-like cells are modulated by TGF-ß signaling.

Desmoid-like fibromatosis (DF) is a rare myofibroblastic benign tumor, often associated with local and repeated injuries, spontaneous regression and stabilization of disease progression suggesting the involvement of altered Wnt/ß-catenin signaling activation and/or aberrant response of the DF cells to external environmental stimuli. The aim of this study was to investigate the response of DF cells to microenvironmental factors such as inflammatory and growth factors or hormones. We observed that the inflammatory cytokine, transforming growth factor-ß (TGF-ß1) stimulated cell growth and myofibroblast differentiation of DF cells regardless of the presence of a ß-catenin mutation. The role of TGF-ß1 in cell growth and myogenic differentiation of in vitro cultures of primary DF cells and normal fibroblasts was investigated by gene and protein expression analyses. We demonstrated that TGF-ß1 exerted its role via the canonical Smad pathway with the phosphorylation of Smad3 being crucial for TGF-ß1 dependent DF cell growth and myofibroblastic differentiation. Furthermore we demonstrated that cell confluence is a critical determinant of TGF-ß1 inducing the DF myofibroblast differentiation, implying that the intercellular communications have an important role on the DF myofibroblast behavior. We observed the formation of an increased stress-fiber pattern in DF cells with increased projected cell area and stronger cell-cell contacts in presence of TGF-ß1. These results demonstrated that TGF-ß1 plays a crucial role in the DF cells growth and, together with cell-cell interactions, in DF myofibroblast conversion; we also highlighted that the cellular sensitivity to this cytokine was an intrinsic feature of the DF cells.

E2F1 germline copy number variations and melanoma susceptibility.

BACKGROUND: Melanoma is an aggressive type of skin cancer whose aetiology remains elusive as both environmental and genetic factors can contribute to its development. Recent studies have demonstrated the existence of multiple copies of E2F1 gene in melanoma specimens which could explain the deregulated E2F1 activity in this type of cancer. This finding suggests a key role for this transcription factor in the malignant transformation of melanocytes. Therefore, E2F1 has been considered as a potential therapeutic target for this form of skin cancer. Since germline copy number variations (CNVs) have been associated with increased susceptibility to different types of cancer, the aim of our study was to assess germline E2F1 CNV in melanoma patients. However, CNVs not necessarily lead to gene dosage imbalance, hence, further factors, in association with CNVs, could contribute to clinical manifestations. Considering that heat stress has been hypothesised as a contributing factor to skin cancer, we also investigated the effect of heat stress on E2F1 expression. METHODS: E2F1 CNV was measured in genomic DNA isolated from blood of 552 patients diagnosed with melanoma and 520 healthy subjects using TaqMan Copy Number Assays. E2F1 mRNA expression was also evaluated by RT-qPCR in the melanoma cell line, SK MEL 267, before and after exposure to heat stress. RESULTS: We found that patients diagnosed with melanoma (1.6%, 9/552) harboured frequently altered germline E2F1 copies compared to healthy subjects (0%, 0/520). Moreover, the difference among the two groups was statistically significant (p = 0.004). Furthermore, we found that heat exposure alone can significantly induce E2F1 expression. CONCLUSIONS: This is the first study that shows a relation between germline E2F1 CNV and melanoma, suggesting that altered copies of this gene might be a predisposing factor to skin cancer. Our results also suggest that environmental insults, such as heat stress, could contribute to an aberrant E2F1 activity by inducing E2F1 mRNA expression. Therefore, subjects with multiple constitutive copies of E2F1 are at greater risk of developing melanoma when exposed to heat. Altogether our results corroborate with the hypothesis that susceptibility to melanoma depends on both the environment and genetic factors.

Orthostatic hypotension and REM sleep behaviour disorder: impact on clinical outcomes in α-synucleinopathies.

OBJECTIVE: Review the effect of orthostatic hypotension (OH) and rapid-eye-movement sleep behavioural disorder (RBD) on survival, cognitive impairment and postural stability, and discuss pathogenic mechanisms involved in the association of these two common non-motor features with relevant clinical outcomes in α-synucleinopathies. METHODS: We searched PubMed (January 2007-February 2019) for human studies of OH and RBD evaluating cognitive impairment, postural instability, and survival in Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and pure autonomic failure (PAF). Included studies were analysed for design, key results and limitations as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: OH and RBD showed a positive association with cognitive impairment in PD and DLB, conflicting association in PAF, and no association in MSA. OH was correlated with incident falls and postural instability in PD and DLB but not in MSA. The association between RBD and postural instability was inconclusive; positive in five studies, negative in seven. OH, but not RBD, correlated with reduced survival in PD, DLB and MSA. The combination of OH and RBD was associated with cognitive impairment and more rapid progression of postural instability. CONCLUSIONS: OH and RBD yielded individual and combined negative effects on disability in α-synucleinopathies, reflecting a 'malignant' phenotype of PD with early cognitive impairment and postural instability. Underlying mechanisms may include involvement of selected brainstem cholinergic and noradrenergic nuclei.

Favorable Prognosis of Wheat Allergy in Adults.

BACKGROUND AND OBJECTIVE: Wheat ingestion can lead to disorders such as IgE-mediated food allergy and wheat-dependent exercise-induced anaphylaxis (WDEIA), both of which are associated with impaired quality of life and significant morbidity. Allergy to wheat is relatively benign in children, although its natural history in adults is still unknown. Objective: We used placebo-controlled challenge to evaluate the natural history of wheat hypersensitivity in atopic patients with adultonset wheat allergy. METHODS: We enrolled 13 patients from an initial cohort of adult patients with IgE-mediated wheat allergy (mean age, 40 years). After diagnosis, the patients observed a wheat-free diet and were followed as outpatients for 5 years to evaluate wheat exposure. Wheat-IgEtiters were determined at the end of follow-up, and a second wheat-challenge was performed. RESULTS: Ten out of 13 patients took part in the study. The mean period of wheat avoidance was 4.2 years. Three patients had spontaneously reintroduced wheat before the second evaluation, after a mean (IQR) of 28 (18-36) months, with only mild gastrointestinal discomfort at reintroduction. At the end of follow-up, 9 of the 10 patients were wheat-tolerant. Two patients had a history of WDEIA. We observed a reduction in IgE levels, with median (IQR) IgE falling from 2.77 (0.35-100) kU/L at diagnosis to 0.88 (0.1-20.8) kU/L. The association between IgE and a negative challenge result was not statistically significant. CONCLUSION: IgE-mediated wheat allergy in adults is benign and represents a temporary break in gastrointestinal tolerance. Future studies may improve our knowledge of wheat allergens, routes of and factors leading to sensitization, and prognostic biomarkers.